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Host protein phosphorylation landscape in A549 cells during influenza A virus entry

ABSTRACT: Influenza A virus (IAV) is a zoonotic pathogen causing respiratory infections in humans and other mammalian species. Besides the potential to cause pandemics, seasonal IAV causes high medical and economical burden due to 3 to 5 million cases of severe respiratory illness and up to 500,000 deaths every year. Increasing resistance against clinically used anti influenza drugs and an insufficient vaccine protection urge the development of new antiviral strategies to counteract this constant threat to global health. One new approach focuses on cellular factors involved in the IAV life cycle as potential drug targets. Particularly promising are kinases and their target proteins, as kinase inhibitors comprise up to 30% of drug discovery programs in the pharmaceutical industry. In this project, we aim to find suitable candidates for the development of host factor targeted antivirals by using state-of-the-art quantitative phosphoproteomics to reveal the unique phosphoproteome dynamics that occur in the host cell within minutes of IAV infection and enable entry of the virus into its host cell. We identified 3,920 host proteins phosphorylated by infection with avian and seasonal human IAV strains. Among them are known entry factors such as the human epidermal growth factor receptor (EGFR) and members of the phosphoinositid-3-kinase (PI3K) pathway, which validate our approach.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Influenza A Virus Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Influenza,Avian Influenza

SUBMITTER: Annika Hunziker

LAB HEAD: Silke Stertz

PROVIDER: PXD029753 | Pride | 2022-01-13

REPOSITORIES: Pride

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			Action	DRS
	A_Brisbane_10_2007_replicate1.raw	Raw
	A_Brisbane_10_2007_replicate2.raw	Raw
	A_Brisbane_10_2007_replicate3.raw	Raw
	A_Brisbane_10_2007_replicate4.raw	Raw
	A_Brisbane_10_2007_replicate5.raw	Raw

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Project description:E2 exposure significantly decreased peak viral titer in hNECs from female donors. We used microarray analyses to identify global gene expression patterns between E2 and vehicle exposed hNECs from female donors Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17Î²-estradiol (E2) or select estrogen receptor modulators (SERMs), then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects where sex-dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor- 2 (ESR2) as neither genomic ESR1 nor non- genomic GPR30 were expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion, but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans. Primary human nasal epithelial cells from females were exposed to E2 for 24h prior to infection, then infected with an H3N2 strain of influenza a virus for 2 hours. At 24 and 48h post infection, hNECs were collected in Trizol for RNA extraction and hybridization on Affymetrix Human Gene ST 2.0 microarrays.

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Host protein phosphorylation landscape in A549 cells during influenza A virus entry

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